scholarly journals A SIRT1-LSD1 Corepressor Complex Regulates Notch Target Gene Expression and Development

2011 ◽  
Vol 42 (5) ◽  
pp. 689-699 ◽  
Author(s):  
Peter Mulligan ◽  
Fajun Yang ◽  
Luisa Di Stefano ◽  
Jun-Yuan Ji ◽  
Jian Ouyang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Notch Target Gene ◽  
Target Gene Expression ◽  
Corepressor Complex

scholarly journals CDK6 kinase activity is required for thymocyte development

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6120-6131 ◽  
Author(s):  
Miaofen G. Hu ◽  
Amit Deshpande ◽  
Nicolette Schlichting ◽  
Elisabeth A. Hinds ◽  
Changchuin Mao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Kinase Activity ◽  
Thymocyte Development ◽  
Hematopoietic Stem ◽  
Notch Target Gene ◽  
Target Gene Expression ◽  
Lymphoid Malignancies ◽  
Proliferation And Differentiation

Abstract Cyclin-dependent kinase-6 (CDK6) is required for early thymocyte development and tumorigenesis. To mechanistically dissect the role of CDK6 in thymocyte development, we generated and analyzed mutant knock-in mice and found that mice expressing a kinase-dead Cdk6 allele (Cdk6K43M) had a pronounced reduction in thymocytes and hematopoietic stem cells and progenitor cells (Lin−Sca-1+c-Kit+ [LSK]). In contrast, mice expressing the INK4-insensitive, hyperactive Cdk6R31C allele displayed excess proliferation in LSK and thymocytes. However, this is countered at least in part by increased apoptosis, which may limit progenitor and thymocyte expansion in the absence of other genetic events. Our mechanistic studies demonstrate that CDK6 kinase activity contributes to Notch signaling because inactive CDK6 kinase disrupts Notch-dependent survival, proliferation, and differentiation of LSK, with concomitant alteration of Notch target gene expression, such as massive up-regulation of CD25. Further, knockout of CD25 in Cdk6K43M mice rescued most defects observed in young mice. These results illustrate an important role for CDK6 kinase activity in thymocyte development that operates partially through modulating Notch target gene expression. This role of CDK6 as a downstream mediator of Notch identifies CDK6 kinase activity as a potential therapeutic target in human lymphoid malignancies.

scholarly journals Notch Activation Is an Early and Critical Event during T-Cell Leukemogenesis in Ikaros-Deficient Mice

2006 ◽  
Vol 26 (1) ◽  
pp. 209-220 ◽  
Author(s):  
Alexis Dumortier ◽  
Robin Jeannet ◽  
Peggy Kirstetter ◽  
Eva Kleinmann ◽  
MacLean Sellars ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Suppressor ◽  
Target Gene ◽  
Critical Role ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Notch Target Gene ◽  
Target Gene Expression ◽  
T Cell Leukemogenesis ◽  
Notch Activation

ABSTRACT The Ikaros transcription factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (IkL/L) in the Ikaros gene all develop thymic lymphomas. IkL/L tumors always exhibit strong activation of the Notch pathway, which is required for tumor cell proliferation in vitro. Notch activation occurs early in tumorigenesis and may precede transformation, as ectopic expression of the Notch targets Hes-1 and Deltex-1 is detected in thymocytes from young IkL/L mice with no overt signs of transformation. Notch activation is further amplified by secondary mutations that lead to C-terminal truncations of Notch 1. Strikingly, restoration of Ikaros activity in tumor cells leads to a rapid and specific downregulation of Notch target gene expression and proliferation arrest. Furthermore, Ikaros binds to the Notch-responsive element in the Hes-1 promoter and represses Notch-dependent transcription from this promoter. Thus, Ikaros-mediated repression of Notch target gene expression may play a critical role in defining the tumor suppressor function of this factor.

scholarly journals Down-regulation of notch target gene expression by suppressor of deltex

2003 ◽  
Vol 255 (2) ◽  
pp. 363-372 ◽  
Author(s):  
Sabine L Mazaleyrat ◽  
Maggy Fostier ◽  
Marian B Wilkin ◽  
Hanna Aslam ◽  
Dana A.P Evans ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Down Regulation ◽  
Notch Target Gene ◽  
Target Gene Expression

scholarly journals Osteogenic Oxysterol, 20(S)-Hydroxycholesterol, Induces Notch Target Gene Expression in Bone Marrow Stromal Cells

2009 ◽  
pp. 091019190442039-37 ◽  
Author(s):  
Woo-Kyun Kim ◽  
Vicente Meliton ◽  
Sotirios Tetradis ◽  
Gerry Weinmaster ◽  
Theodore J Hahn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Target Gene ◽  
Marrow Stromal Cells ◽  
Notch Target Gene ◽  
Target Gene Expression

scholarly journals Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone α

2021 ◽  
Author(s):  
Beatriz Romartinez-Alonso ◽  
Maura Agostini ◽  
Heulyn Jones ◽  
Jayde McLellan ◽  
Deepali Sood ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Transcriptional Repression ◽  
Target Gene ◽  
Thyroid Hormone Receptor ◽  
Activation Function ◽  
Zebrafish Model ◽  
Target Gene Expression ◽  
Corepressor Complex ◽  
Thyroid Hormone Receptor Α

Mutations in thyroid hormone receptor α (TRα), a ligand-inducible transcription factor, cause Resistance to Thyroid Hormone α (RTHα). This disorder is characterised by tissue-specific hormone refractoriness and hypothyroidism, due to inhibition of target gene expression by mutant TRα-corepressor complexes. Using biophysical approaches, we show that RTHα-associated TRα mutants devoid of ligand-dependent transcription activation function, unexpectedly retain the ability to bind thyroid hormone. Visualisation of ligand (T3) within the crystal structure of a prototypic TRα mutant, validates this notion. This finding prompted synthesis of different thyroid hormone analogues, identifying a lead compound (ES08) which dissociates corepressor from mutant human TRα more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHα and induces target gene expression in TRα mutation-containing cells from an RTHα patient, more effectively than T3. Our observations provide proof-of-principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRα-corepressor complex, for treatment of RTHα.

scholarly journals Local overexpression of Su(H)-MAPK variants affects Notch target gene expression and adult phenotypes in Drosophila

Data in Brief ◽  
2015 ◽  
Vol 5 ◽  
pp. 852-863 ◽  
Author(s):  
Jasmin S. Auer ◽  
Anja C. Nagel ◽  
Adriana Schulz ◽  
Vanessa Wahl ◽  
Anette Preiss
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Notch Target Gene ◽  
Target Gene Expression

scholarly journals Glucocorticoids inhibit notch target gene expression in osteoblasts

2018 ◽  
Vol 119 (7) ◽  
pp. 6016-6023 ◽  
Author(s):  
Stefano Zanotti ◽  
Jungeun Yu ◽  
Suyash Adhikari ◽  
Ernesto Canalis
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Notch Target Gene ◽  
Target Gene Expression
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